Imiquimod-Tretinoin-Levocetir (imiquimod/tretinoin/levocetirizine dihydrochloride)

Excessive application of tretinoin does not increase the therapeutic effects of the drug and may produce marked inflammatory reactions, including peeling and discomfort.

Because of the potential for adverse local reactions (e.g., erythema, erosion, excoriation/flaking, edema), the recommended dose, frequency of application, and duration of treatment of topical imiquimod should not be exceeded; use of excessive amounts of the cream should be avoided. Topical imiquimod therapy may be temporarily discontinued for several days if required because of the patient's discomfort or severity of local reactions, and then reinitiated after the reactions subside. However, the total duration of treatment should not be extended beyond the maximum recommended duration (i.e., 16 weeks for treatment of actinic keratosis, 6 weeks for treatment of superficial basal cell carcinoma, 16 weeks for treatment of genital and perianal HPV warts).

Tretinoin is applied topically to the skin as a cream, gel, or solution. Patients should be instructed carefully in proper use of the drug, including associated precautions. (See Cautions: Precautions and Contraindications and also Drug Interactions.)

Imiquimod is applied topically as a 5% cream.

The topical cream is for external use only. Contact with the eyes, lips, and nostrils should be avoided and the drug should not be administered orally, intravaginally, or intra-anally.

Imiquimod is suitable for self-administration. Prior to initial use, patients should be instructed regarding proper techniques for application and removal of the drug.

Patients should be directed to wash their hands before and after applying imiquimod cream. Prior to application, the affected area should be washed with mild soap and water and allowed to dry thoroughly (at least 10 minutes). Immediately prior to normal sleeping hours (bedtime) on treatment days, the cream should be applied to the entire treatment area and rubbed in until no longer visible. The cream should be allowed to remain on the skin for approximately 8 hours (6-10 hours) and removed the following morning by washing with mild soap and water.

When the drug is used for the treatment of genital HPV warts, uncircumcised males should be advised to clean under the foreskin before treatment and once daily during treatment and females should be advised to avoid intravaginal application and take special care when applying near the vaginal opening since local reactions at this site may result in pain or swelling and difficult urination.

Use of imiquimod should be delayed until skin has healed from any previous sunburn or drug or surgical treatment.

Occlusive dressings or wrappings should not be used.

Imiquimod cream is supplied in single-use packets containing 250 mg of cream (12.5 mg of imiquimod). When treating actinic keratosis, no more than 1 packet of the cream should be applied to the contiguous treatment area. When treating external genital or perianal human papillomavirus (HPV) warts, 1 packet of cream should be sufficient to cover a wart area up to 20 cm2. Partially used packets should be discarded and should not be reused.

No dosing information is available for this tab.

No dosing information is available for this tab.

Concomitant use of tretinoin with other topical medications (especially those containing keratolytic agents such as sulfur, resorcinol, benzoyl peroxide, or salicylic acid) should be undertaken with caution because of the possibility of interactions. In patients who have used keratolytic agents, sufficient time should elapse for the effects of these drugs to subside before initiating tretinoin therapy. Patients receiving tretinoin therapy should not wash their faces more frequently than 2 or 3 times daily, using a mild, bland soap. Medicated or drying soaps and abrasive soaps and cleansers generally should not be used. Use of topical preparations with high concentrations of alcohol, menthol, spices, or lime such as shaving lotions, astringents, and perfume should be avoided, since they may cause stinging of treated skin, especially during initial therapy. Patients also should avoid the use of irritating cosmetics (e.g., toners, peeling (desquamating) agents), permanent wave solutions, electrolysis, or hair depilatories during topical tretinoin therapy. Non-medicated cosmetics may be used by patients receiving tretinoin therapy, but the areas to be treated should be cleansed thoroughly before tretinoin is applied; medicated cosmetics should not be used.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

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There are no contraindication contraindications for this drug.

• Eczema
• Graft-versus-host disease
• Skin photosensitivity
• Sunburn

• Autoimmune disease
• Immunosuppression

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More Frequent

• Blistering skin
• Fungal infection
• Skin crusting
• Superficial skin ulcer

Less Frequent

• Severe erythema
• Squamous cell carcinoma
• Tinea cruris

Rare or Very Rare

• Abnormal hepatic function tests
• Acute myocardial infarction
• Agitation
• Angioedema
• Arthralgia
• Blistering skin
• Bone marrow depression
• Depression
• Dyspnea
• Dysuria
• Flu-like symptoms
• Heart failure
• IgA vasculitis
• Insomnia
• Malignant lymphoma
• Proteinuria
• Syncope
• Thyroiditis
• Urinary retention

More Frequent

• Abnormal desquamation
• Dry skin
• Erythema
• Erythema
• Induration of skin
• Pruritus of skin
• Pruritus of skin
• Skin inflammation
• Skin inflammation
• Skin irritation
• Skin photosensitivity
• Skin rash
• Skin swelling
• Stinging of skin
• Treatment site sequelae
• Upper respiratory infection

Less Frequent

• Back pain
• Diarrhea
• Dry skin
• Edema
• Fatigue
• Fever
• Headache disorder
• Localized edema
• Skin hypopigmentation
• Skin photosensitivity
• Stinging of skin

Rare or Very Rare

• Abdominal pain with cramps
• Alopecia
• Chills
• Dizziness
• Dyschromia
• Eczema
• Herpes simplex infection
• Sinusitis
• Vomiting
• Vulvar edema

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Retinoids (e.g., isotretinoin) have been reported to cause serious fetal harm when administered to pregnant women. (See Cautions: Pregnancy, Fertility, and Lactation, in Isotretinoin 84:36.) Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters, and subhuman primates. Tretinoin was teratogenic in Wistar rats when given orally or topically in dosages exceeding 1 mg/kg daily (8 times the maximum human systemic dosage normalized for total body surface area). In the cynomolgus monkey, which metabolically is closer to humans for tretinoin than other species examined, fetal malformations were reported at oral dosages of 10 mg/kg daily or greater, but none were observed at 5 mg/kg daily (83 times the maximum human systemic dosage normalized for total body surface area), although increased skeletal variations were observed at all dosages. Dose-related increased embryolethality and abortion also were reported. Similar results also have been reported in pigtail macaques.

Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at dosages exceeding 1 mg/kg daily (8 times the maximum human systemic dosage normalized for total body surface area). Bone anomalies (short (13%) or bent (6%) humerus, incompletely ossified os parietal (14%)) also have been reported in rats when tretinoin 10 mg/kg daily was applied dermally. Topical tretinoin cream was associated with an increased incidence of cleft palate and hydrocephaly in rabbits when administered in a dosage 91 times the topical human dosage (based on topical application of 1 g of 0.1% tretinoin cream in a 50-kg adult). In New Zealand white rabbits treated with topical tretinoin at dosages 80 times the recommended human topical clinical dosage, an increased incidence of domed head and hydrocephaly was noted in some of the fetuses, typical of retinoid-induced fetal malformations in this species; no abnormalities were observed at dosages 3 times the maximum human systemic dosage of tretinoin after topical administration of 0.1% tretinoin gel (microsphere formulation), normalized for total body surface area. In addition, topical tretinoin in formulations other than the gel (microsphere formulation) was not teratogenic when given in dosages of 42 or 27 times the maximum human systemic topical dosage in rats or rabbits, respectively. However, delayed ossification of several bones, occurred in rabbits and a dose-dependent incease in supernumerary ribs was observed in rats at these topical dosages.

Oral tretinoin was fetotoxic in rats at dosages 21 times the maximum human systemic dosage normalized for total body surface area, resulting in skeletal variations and increased intrauterine death in rats. Topical tretinoin has been shown to be fetotoxic in rabbits when administered in dosages 8 times the maximum human systemic dosage applied topically and normalized for total body surface area), resulting in fetal resorption and variations in ossification.

When given subcutaneously to rabbits, tretinoin was teratogenic at a dosage of 2 mg/kg daily but not at 1 mg/kg daily. These dosages are approximately 400 and 200 times, respectively, the human topical dosage of tretinoin cream (based on topical application of 1 g of 0.025% tretinoin cream in a 50-kg adult).

With widespread use of any drug, a small number of birth defect reports associated with the administration of the drug would be expected by chance alone. During 2 decades of clinical use of one formulation of topical tretinoin (Retin-A(R)), 30 cases of temporally associated congenital malformations have been reported. Although no definite pattern of teratogenicity and no causal associations have been established from these cases, 5 of the reports described the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The relevance of these spontaneous reports in terms of risk to the fetus is unknown.

To date, there have been no adequate and well-controlled studies performed in pregnant women, and the teratogenic blood level of tretinoin is not known. The manufacturer of some topical tretinoin preparations (e.g., Retin-A(R)) state that topical tretinoin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, while manufacturers of other tretinoin formulations (e.g., Avita(R) cream, Renova(R) emollient cream) state that these products should not be used during pregnancy.

There was no evidence of embryotoxicity or teratogenicity when oral imiquimod was used in rats and rabbits at dosages 98 times the maximum recommended human dose (MRHD) (based on area under the plasma concentration-time curve (AUC) comparisons) or when IV imiquimod was used in rabbits at dosages 407 times the MRHD (based on AUC) or 1.5 times the MRHD (based on body surface area). When oral imiquimod dosages 577 times the MRHD (based on AUC) were used in rats, maternal toxicity occurred and adverse fetal effects included increased resorptions, decreased fetal body weight, delayed skeletal ossification, bent limb bones, and exencephaly, protruding tongues, and low-set ears. There are no adequate and controlled studies using imiquimod in pregnant women, and the drug should be used during pregnancy only when clearly needed.

It is not known whether topically applied tretinoin is excreted in human milk. Caution should be exercised when topical tretinoin is administered to a nursing woman.

It is not known whether topically applied imiquimod is distributed into human milk. The drug should be used with caution in nursing women.

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